The Department of Health asked the National Institute for Health and Clinical Excellence (NICE or the Institute) to conduct a single technology appraisal (STA) of rituximab for the first-line treatment of chronic lymphocytic leukaemia and provide guidance on its use to the NHS in England and Wales. The Appraisal Committee has had its first meeting to consider both the evidence submitted by the manufacturer and the views put forward by non-manufacturer consultees and commentators, and by the clinical specialist and patient expert representatives nominated for this appraisal by non-manufacturer consultees and commentators. The Committee has developed preliminary recommendations on the use of rituximab.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website, www.nice.org.uk). This document should be read in conjunction with the evidence base for this appraisal (the evaluation report) which is available from www.nice.org.uk

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. For further details, see the ‘Guide to the single technology appraisal process’ (this document is available on the Institute’s website, www.nice.org.uk).

• The Appraisal Committee will meet again to consider the original evidence and this appraisal consultation document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the final appraisal determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute’s guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: 20 April 2009

Second Appraisal Committee meeting: 6 May 2009

Details of membership of the Appraisal Committee are given in appendix A, and a list of the sources of evidence used in the preparation of this document is given in appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in section 1 are preliminary and may change after consultation.

1  Appraisal Committee’s preliminary recommendations

1.1 Rituximab in combination with fludarabine and cyclophosphamide is recommended as an option for the first-line treatment of people with chronic lymphocytic leukaemia for whom fludarabine in combination with cyclophosphamide is considered appropriate.

1.2 The use of rituximab for the first-line treatment of chronic lymphocytic leukaemia in combination with chemotherapeutic agents other than fludarabine and cyclophosphamide is not recommended.

 

2 The technology

2.1 Rituximab (MabThera, Roche) is a chimeric monoclonal antibody that binds selectively to the CD20 antigen expressed on the surface of mature B lymphocytes and tumour cells that express CD20. Rituximab is licensed for the first-line treatment of people with chronic lymphocytic leukaemia in combination with chemotherapy. Rituximab is administered intravenously, once every 4 weeks for a total of six cycles; a complete course of treatment with rituximab lasts 24 weeks. Dosing is calculated according to body surface area, with an initial dose of 375 mg/m² followed by 500 mg/m² for all subsequent doses. Six cycles of rituximab equate to a total dose of 2875 mg/m².

2.2 The most frequently observed adverse events in people receiving rituximab are infusion-related reactions, including cytokine release syndrome. The majority of these reactions occur during the first infusion. Serious but rare adverse events associated with rituximab include neutropenia and leucopenia (including febrile neutropenia), infections (predominantly bacterial and viral) and cardiovascular events (hypotension, hypertension, arrhythmias and angina). Very rare serious adverse events include hepatitis B reactivation and progressive multifocal leucoencephalopathy. For full details of side effects and contraindications, see the summary of product characteristics.

2.3 Rituximab is available in 100 mg (10 ml) and 500 mg (50 ml) vials. The cost of a 100 mg vial is £174.63, and of a 500 mg vial is £873.15 (excluding VAT; British National Formulary [BNF] edition 57). For a person with a body surface area of 1.93 m², the cost of rituximab for the first dose is £1397 and for subsequent doses £1746 including wastage of excess rituximab. The total cost of rituximab is £10,128 per course. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturer’s submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of rituximab for the first-line treatment of chronic lymphocytic leukaemia and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The manufacturer’s submission compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide combination therapy. This comparison was based on the CLL-8 trial, a phase III randomised controlled trial. The CLL-8 trial was a multicentre, open-label, parallel-group study in people with previously untreated chronic lymphocytic leukaemia. In the CLL-8 trial a total of 817 people were randomised to receive either fludarabine and cyclophosphamide or rituximab in combination with fludarabine and cyclophosphamide; data were reported on 810 people. The median age of trial participants was 61 years and 74% of participants were men. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 95% of participants were Binet stage B or C disease. People with Binet stage A disease (n = 40) were enrolled into the trial until a protocol amendment stopped further enrolment.

3.2 Trial participants were randomised to six cycles of treatment, with an interim staging after three cycles. People with progressive or stable disease at interim staging were offered alternative treatments by their clinicians outside the trial. People in the control group whose disease did not respond to treatment did not cross over to the treatment group, but could be offered rituximab-containing regimens. People whose disease showed a partial or complete response at the interim staging received all six cycles of treatment. Each cycle of 28 days consisted of fludarabine and cyclophosphamide chemotherapy (fludarabine [25 mg/m²] and cyclophosphamide [250 mg/m²] on days 1, 2 and 3) with or without rituximab (375 mg/m² on day 0 of cycle 1, 500 mg/m² on day 1 of cycles 2‑6). All trial treatments were administered intravenously.

3.3 The primary outcome of the trial was progression-free survival defined as the time between randomisation and the date of the first documented disease progression, relapse or death by any cause. Secondary outcomes were event-free survival, overall survival, disease-free survival, duration of response, time to new chronic lymphocytic leukaemia treatment and response rates. Quality of life data were collected in the trial using the Spitzer Quality of Life Index and the European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 30 (EORTC-QLQC30).

3.4 Demographic characteristics and disease characteristics, including Binet stage B symptoms and prognostic markers such as cytogenetic abnormalities, were well balanced between the trial groups. Of all trial participants, 64% had Binet stage B disease, 31% had Binet stage C disease, and 5% Binet stage A disease. The trial also enrolled 46 people (8%) with p53 deletion , a chromosome abnormality associated with a poorer prognosis.

3.5 A pre-planned interim analysis of the trial data after a median follow-up of 20.7 months showed a statistically significant difference in progression-free survival between the treatment groups. At this point the trial was halted and the interim analysis became the main analysis. The reported median progression-free survival was 39.8 months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.2 months in the fludarabine and cyclophosphamide group with a hazard ratio of 0.56 (95% CI, 0.43 to 0.72, p < 0.0001). The trial also reported an overall response rate of 86.1% in the rituximab in combination with fludarabine and cyclophosphamide group and 72.7% in the fludarabine and cyclophosphamide group. At this point median overall survival had not been reached and the trial reported a hazard ratio of 0.64 (95% CI, 0.41 to 1.00; p = 0.05).

3.6 The manufacturer also submitted analyses of data from the CLL-8 trial collected from three follow-up points of a longer duration.  After a median duration of follow-up of 25.4 months, the reported median progression-free survival was 42.8 months in the rituximab in combination with fludarabine and cyclophosphamide group and 32.5 months in the fludarabine and cyclophosphamide group with a hazard ratio of 0.60 (95% CI, 0.48 to 0.76; p<0.001). At the end of this follow-up period the statistically significant difference in overall survival was not maintained (hazard ratio 0.72, 95% CI 0.48 to 1.09; p = 0.13). However, the data remained highly censored, because the majority of people were still alive. A further analysis after a median follow-up of 25.5 months reported a rate of progression-free survival of 76.6% in the rituximab in combination with fludarabine and cyclophophamide group and 62.3% in the fludarabine and chclophosphamide group (p<0.001). At this follow-up point, the CLL-8 trial reported an overall response rate of 95% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p=0.001). The overall survival rate was 91% in the rituximab in combination with fludarabine and cyclophosphamide group and 88% in the fludarabine and cyclophosphamide group (p=0.18). In a further analysis after a median follow-up of 26.4 months the reported mean progression-free survival was 37.1 months in the rituximab in combination with fludarabine and cyclophosphamide group and 30.8 months in the fludarabine and cyclophosphamide group (p < 0.001). The hazard ratio for progression-free survival was 0.6 (95% CI 0.47 to 0.75; p < 0.0001). Mean overall survival was 47.7 months in the rituximab in combination with fludarabine and cyclophosphamide group and 48.2 months in the fludarabine and cyclophosphamide group (p = 0.18).

3.7 The manufacturer presented a number of subgroup analyses. For the people with the p53 mutation the hazard ratio for progression-free survival was 0.6 (95% CI 0.31 to 1.19). The hazard ratio for progression-free survival for people with Binet stage A disease was 0.13 (95% CI 0.03 to 0.61, p = 0.01), Binet stage B disease was 0.46 (95% CI 0.32 to 0.63, p < 0.0001) and Binet stage C disease was 0.88 (95% CI 0.58 to 1.33, p = 0.54). The CLL-8 trial was not powered to detect differences in treatment effect for any of these subgroups.

3.8 In the CLL-8 trial, 77% of people in the rituximab in combination with fludarabine and cyclophosphamide group experienced a grade 3 or 4 adverse event compared with 62% in the fludarabine and cyclophosphamide group. In the rituximab in combination with fludarabine and cyclophosphamide group 46% of people experienced a serious adverse event; this figure was 41% of people in the fludarabine and cyclophosphamide group. The main adverse events were haematological toxicities, with neutropenia, leucopenia, febrile neutropenia and pancytopenia having a higher incidence (at least 2% difference) in the rituximab in combination with fludarabine and cyclophosphamide group, and thrombocytopenia, anaemia and pyrexia having a higher incidence (at least 2% difference) in the fludarabine and cyclophosphamide group. There were no differences in the rate of other adverse events between the trial groups.

3.9 The manufacturer provided data from four uncontrolled phase II trials on the efficacy and tolerability of combining rituximab with different chemotherapy regimens. The combination chemotherapies included fludarabine, pentostatin, cyclophosphamide and mitoxantrone for the first-line treatment of chronic lymphocytic leukaemia. One of the studies (n = 300) compared a group of people treated with rituximab in combination with fludarabine and cyclophosphamide with a group of people who had been treated with fludarabine-based regimens in the past and provided data with a median follow-up of 6 years. For the group receiving rituximab the rate of overall survival after six years was 77% with a 95% overall response rate. Median time to progression was 80 months. In comparison with the historical control group, rituximab in combination with fludarabine and cyclophosphamide was associated with statistically significant overall survival and was the strongest independent predictor of survival (hazard ratio 0.48, p < 0.001).

3.10 In their submission, the manufacturer also compared rituximab in combination with fludarabine and cyclophosphamide with chlorambucil using a mixed treatment comparison. A mixed treatment comparison was conducted because there were no head-to-head studies comparing rituximab with comparators other than fludarabine and cyclophosphamide. As well as chlorambucil, this analysis also included alemtuzumab, fludarabine alone and bendamustine. In addition to CLL-8, a further seven trials were identified and used to create a network of evidence to make indirect comparisons of rituximab in combination with fludarabine and cyclophosphamide with the other comparators. The studies were combined using a fixed effect model because there was no apparent gain in goodness of fit when a random effects model was used. The mixed treatment comparison showed that chlorambucil had the shortest progression-free survival and therefore this was used as the reference treatment. The mean hazard ratios for other treatments compared with chlorambucil were 0.24 for rituximab in combination with fludarabine and cyclophosphamide, 0.43 for fludarabine and cyclophosphamide, 0.59 for alemtuzumab and 0.86 for fludarabine alone. The mean hazard ratio for progression-free survival was 0.56 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide, 0.24 for rituximab in combination with fludarabine and cyclophosphamide compared with chlorambucil, 0.42 for rituximab in combination with fludarabine and cyclophosphamide compared with alemtuzumab and 0.28 for rituximab in combination with fludarabine and cyclophosphamide compared with fludarabine alone.

3.11 The manufacturer’s submission presented an economic analysis comparing rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide, and rituximab in combination with fludarabine and cyclophosphamide with chlorambucil. The manufacturer developed a three-state Markov model with a cycle length of 1 month and a 15-year time horizon (to represent a lifetime horizon). The health states in the model were ‘progression-free survival’, ‘progressed’, or ‘death’. People entered the model in the progression-free survival health state. The probability of transition from the progression-free survival to the progressed health state was taken from the groups in CLL-8. For the transition from the progression-free survival to the death health state, trial data was used supplemented with Office of National Statistics data to inform the background mortality rate. Transition from the progressed to the progression-free survival health state was not possible. For the transition from the progressed to the death health state, data for people from both groups of the trial were aggregated and a single probability from the trial applied as there was a non-significant difference in overall survival between the groups in the trial.

3.12 In the model the drug costs were calculated assuming a body surface area of 1.93 m² which reflects the average body surface area of the people in the CLL-8 trial. The CLL-8 trial used fludarabine and cyclophosphamide administered intravenously, but it is more common to use oral chemotherapy in the UK. In the model it was assumed that the efficacy of fludarabine and cyclophosphamide is the same regardless of the route of administration if the dosage is adjusted to ensure equivalent bioavailability. The costs of the drug in the model were adjusted to allow for the difference in the route of administration. The drug costs for rituximab were £1397 for the first cycle of treatment and £1746 for subsequent cycles. For six cycles of treatment the total drug cost of rituximab was £10,128. The total drug costs of fludarabine, cyclophosphamide and chlorambucil were calculated as £2790, £22 and £286, respectively. In the base case, all people receive six cycles of therapy unless disease progression occurs before the end of the six cycles.

3.13 The model included costs for supportive care that varied between the health states. This included costs for blood transfusions and bone marrow transplant in the progression-free survival health state taken from the CLL-8 trial and costs for second-line therapies for the progressed health state. In the model rituximab had a cost for intravenous administration of £430 per cycle of treatment and the cost for an appointment to prescribe oral fludarabine and cyclophosphamide chemotherapy was £280. It was assumed that oral chemotherapy could be prescribed in the same appointment as rituximab so no additional cost of prescribing oral chemotherapy was included for the rituximab treatment group. Costs were also added for the pharmacist’s time to prepare the infusion.

3.14 The utility values used in the manufacturer’s submission were taken from a previous Health Technology Assessment report (Hancock et al. 2002) that assessed the cost effectiveness of fludarabine as a first-line treatment for chronic lymphocytic leukaemia. A utility of 0.8 was attached to the progression-free survival health state and 0.6 to the progressed health state. The estimates of utility were not preference based, and were estimated by the authors of the Health Technology Assessment report from condition-specific health-related quality of life data. No disutility for adverse events was included in the model. The manufacturer provided an interim analysis of 11 people from an observational study of utility in people with chronic lymphocytic leukaemia. The value for progression-free survival was consistent with that used in the manufacturer’s submission. No conclusions could be drawn about the utility value appropriate for the progressed health state, as data for only two people were available.

3.15 The manufacturer provided a base-case estimate of incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with fludarabine and cyclophosphamide. The incremental quality-adjusted life year (QALY) gain was 0.88 at an incremental cost of £11,617, giving an incremental cost-effectiveness ratio (ICER) of £13,189 per QALY gained. The probabilistic sensitivity analysis presented suggested that rituximab in combination with fludarabine and cyclophosphamide had a 91.9% probability of being cost effective at £20,000 and 98.6% probability of being cost effective at £30,000 when compared with fludarabine and cyclophosphamide. The manufacturer also provided an estimate of the incremental cost effectiveness of rituximab in combination with fludarabine and cyclophosphamide in comparison with chlorambucil. The incremental QALY gain was 1.91 at an incremental cost of £12,250, giving an ICER of £6,422 per QALY gained. Probabilistic sensitivity analysis suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective in comparison with chlorambucil was100% at both the £20,000 and £30,000 per QALY gained.  

3.16 A sensitivity analysis was presented in the manufacturer’s submission using different parametric models for the progression-free survival extrapolation. Additional sensitivity analyses were completed as follows:

• including costs for adverse events
• including costs for febrileneutropeniaepisodes (as in CLL-8)
• increasing and decreasing supportive care costs for the health states by 50%
• assuming utility values for the health states such that the difference in the values between the health states was 0.4 and 0.1.

The assumption of a similar rate of adverse events for chlorambucil and fludarabine and cyclophosphamide was tested by assuming no bone marrow transplants, fewer transfusions and less febrileneutropenia for the chlorambucil arm. One-way sensitivity analyses suggested that the results were not sensitive to a variety of parameter assumptions including utility values, monthly supportive care costs and drug administration costs. The results were sensitive to the function used to extrapolate progression-free survival (exponential,Gompertz), and the highest ICER reported (using a Gompertz function) was £22,661 per QALY gained.

3.17 The manufacturer’s submission also included a scenario analysis to explore the impact on the ICER of using intravenous administration of fludarabine and cyclophosphamide chemotherapy instead of oral administration. This analysis demonstrated that the ICER was not sensitive to assumptions about the mechanism of administration. A further scenario analysis modelled the cost effectiveness of rituximab in combination with chemotherapies other than fludarabine and cyclophosphamide. The results of this analysis suggested that the QALY gain from combining rituximab with chemotherapy would need to decrease to about 40% of that in the base case, all else remaining the same, for the ICER for rituximab to increase to over £30,000 per QALY gained.

3.18  At the request of the ERG the manufacturer performed a further one-way sensitivity analysis to explore the impact on the ICER of using alternative assumptions about different mortality rates between the progression-free survival and progressed health states. The manufacturer increased the mortality rate in the rituximab in combination with fludarabine and cyclophosphamide group by 315% so that the life years gained in both treatment groups were the same (0.24 QALYs). In this scenario the incremental QALY gain was 0.24 at an incremental cost of £7226, giving an ICER of £30,336 per QALY gained.

3.19 The ERG considered that all the relevant studies had been identified. The ERG noted that the manufacturer’s submission was based on only one completed clinical trial, and that this was unpublished. However, it considered this study to be of good quality. In addition, it noted that this study used intravenous administration of fludarabine and cyclophosphamide rather than oral administration which is normally used in UK clinical practice. The ERG considered the study population was appropriate, noting that the subgroup of people with chronic lymphocytic leukaemia and the p53 deletion was only considered in relation to progression-free survival and not assessed in the cost-utility model. The ERG considered that the main comparators used in the cost-effectiveness analysis (fludarabine and cyclophosphamide, and chlorambucil) were appropriate. It noted that the mixed treatment comparison provided estimates of clinical effectiveness comparing rituximab in combination with fludarabine and cyclophosphamide with additional comparators, including alemtuzumab, fludarabine monotherapy and bendamustine. The ERG considered that the mixed treatment comparison completed by manufacturer was appropriate.

3.20 The ERG considered that in the manufacturer’s economic model the fact that people in the progressed health state of chronic lymphocytic leukaemia could not move back into the progression-free survival health state was unrealistic due to the natural history of chronic lymphocytic leukaemia; people with chronic lymphocytic leukaemia may receive further treatment at progression which may then result in further periods of progression-free survival. The relapsing nature of chronic lymphocytic leukaemia means that subsequent periods of progression are less likely to respond to further treatment, implying that later periods of progression in the course of disease are likely to be associated with higher disease-related mortality. Therefore, the ERG considered that the manufacturer’s assumption of a constant hazard of death after progression may not be appropriate. The ERG highlighted that the overall effect of the aggregated progressed health state and constant hazard of death from this health state was to imply a correlation between progression-free survival and overall survival which it did not consider had been empirically demonstrated in the manufacturer’s submission. The ERG further considered that the sensitivity analyses presented by the manufacturer did not fully investigate the uncertainty associated with the extent to which gains in progression-free survival led to gains in overall survival.

3.21 The ERG performed an exploratory analysis of the comparison of rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. First, it conducted a component analysis to examine the relative contributions to utility gain from the gain in progression-free survival and the gain in overall survival. This analysis showed that progression-free survival contributed to 0.24 QALYs and overall survival to 0.64 QALYs (of a total gain of 0.88 QALYs). The ERG concluded that this demonstrated that in the model the majority of the benefit is derived from overall survival making it sensitive to changes in assumptions about overall survival benefits from rituximab. The ERG noted that within the model, because a single transition probability is attached to all people in the progressed health state, the benefit in overall survival is derived almost entirely from the different rate of transfer from the progression-free survival health state to the progressed health state.

3.22 The ERG repeated the analysis completed by the manufacturer (see section 3.18) that removed the differences in survival between the two groups in the model. This was done by decreasing the probability of death in the progressed health state for the fludarabine and cyclophosphamide group. A decrease in the probability of death in the fludarabine and cyclophosphamide group to 57% of the base-case level removed the difference in overall survival between the groups and resulted in a QALY gain of 0.24 at an incremental cost of £7228 and an ICER of £30,304 per QALY gained. When assuming no difference in overall survival between the two treatment groups in the analysis the results suggested that the probability of rituximab in combination with fludarabine and cyclophosphamide being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY was 29% and at £30,000 per QALY gained was 49%. The ERG identified that if it is assumed that there is no difference in overall survival between the rituximab in combination with fludarabine and cyclophosphamide and fludarabine and cyclophosphamide groups, the model outputs become sensitive to the assumed utility differences between the progression-free survival and the progressed health states. If the difference in utility between the health states is reduced by 0.1 (that is from 0.2 to 0.1), the ICER increases to £60,302 per QALY gained.

3.23 The ERG completed another exploratory analysis that assumed that the actual survival benefit from treatment with rituximab was somewhere between the manufacturer’s base case and the assumption of no survival benefit. The ERG incorporated this assumption into the probabilistic sensitivity analysis by adding an additional variable, in which the decrease in probability of death in the fludarabine and cyclophosphamide group was sampled as a uniform distribution between 1 and 0.574. The results suggested that rituximab in combination with fludarabine and cyclophosphamide had a 72% probability of being cost effective compared with fludarabine and cyclophosphamide at £20,000 per QALY gained and 88% probability of being cost effective at £30,000 per QALY gained.

3.24 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/TAxxx

 

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rituximab for the treatment of chronic lymphocytic leukaemia, having considered evidence on the nature of the condition and the value placed on the benefits of rituximab by people with chronic lymphocytic leukaemia, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources.

Clinical effectiveness

4.2 The Appraisal Committee discussed current standard clinical management of people with chronic lymphocytic leukaemia. The Committee heard from clinical specialists that approximately 90% of people with chronic lymphocytic leukaemia are asymptomatic and that diagnosis may be made simply as a chance finding on routine blood testing. People who are asymptomatic may not need immediate treatment, although a proportion of these will do so later in life. The Committee heard that fludarabine in combination with cyclophosphamide is frequently used for people who need immediate treatment. However, chlorambucil alone is normally used for older and frailer people and for people with comorbidities, especially impaired renal function. The Committee heard from patient experts that people with chronic lymphocytic leukaemia who need treatment will often have a series of treatments following first-line treatment with further lines of treatment used after each relapse. The Committee specifically considered the clinical management of people whose chronic lymphocytic leukaemia has the p53 mutation. The Committee heard from clinical specialists that these people have a poorer prognosis and are usually treated with alternative treatments (for example, alemtuzumab) rather than chemotherapy.

4.3 The Committee noted that the evidence of clinical effectiveness was based mainly on a single unpublished randomised controlled trial (the CLL-8 trial) which compared rituximab in combination with fludarabine and cyclophosphamide with fludarabine and cyclophosphamide. The Committee accepted that the CLL-8 trial demonstrated a benefit in progression-free survival, and increased overall and complete response rates for rituximab. The Committee heard from clinical specialists that the CLL-8 trial population was younger and fitter than the population of people with chronic lymphocytic leukaemia seen in routine practice within the NHS in England and Wales. However, for the study population fludarabine in combination with cyclophosphamide was the appropriate comparator, and these people reflected the group who would receive fludarabine in combination with cyclophosphamide in clinical practice. The Committee noted that an interim analysis of the clinical trial results had demonstrated a statistically significant gain in overall survival but this gain had not been maintained during longer follow up. The Committee accepted that crossover and subsequent lines of treatment in the trial made the overall survival benefit difficult to prove. The Committee heard expert opinion that the degree of response to treatment and the duration of progression-free survival were generally accepted as surrogates for overall survival. In addition, the Committee heard that cohort studies using historical controls had also shown survival benefits for people treated with rituximab-containing regimens, although results may have been influenced by changing clinical management such as earlier identification of people with chronic lymphocytic leukaemia. On balance, the Committee was persuaded that the benefits observed in progression-free survival and response rate were likely to lead to a gain in overall survival, although currently this was difficult to quantify.

4.4 The Committee recognised that the manufacturer had also provided evidence from uncontrolled phase II trials that reported the benefits of adding rituximab to other chemotherapy regimens for the first-line treatment of people with chronic lymphocytic leukaemia. The Committee discussed the methodological limitations of obtaining an estimate of clinical effectiveness from uncontrolled and historical comparison studies. The Committee additionally specifically discussed whether rituximab would be added to chlorambucil in clinical practice. The Committee heard from clinical specialists that they considered that there was no evidence to support adding rituximab to chlorambucil, but that there was an ongoing trial investigating this. The Committee concluded that there was considerable uncertainty about the clinical benefit associated with adding rituximab to chemotherapy regimens other than fludarabine and cyclophosphamide.

4.5 The Committee was aware that fludarabine and cyclophosphamide were administered intravenously in the CLL-8 trial. It heard from clinical specialists that these chemotherapy agents were routinely administered orally in the NHS. The Committee accepted that the efficacy of both methods of administration was equivalent as long as doses were adjusted to ensure equivalent bioavailability.

4.6 The Committee heard from patient experts that progression-free survival was associated with a marked improvement in quality of life compared to the symptomatic progressed state. Patient experts commented that the first treatment-induced remission was likely to be the longest and associated with the most substantial improvements in quality of life. For this reason people with chronic lymphocytic leukaemia valued having a choice of first-line treatment options.

Cost effectiveness

4.7 The Committee discussed the economic model submitted by the manufacturer. It noted that the manufacturer had only presented estimates of cost effectiveness for rituximab in combination with fludarabine and cyclophosphamide, and that this was compared with fludarabine in combination with cyclophosphamide and chlorambucil monotherapy. The Committee heard from clinical specialists that for those people for whom chlorambucil was the most appropriate treatment (that is, people who are frail or who have comorbidities), rituximab in combination with fludarabine and cyclophosphamide would not be considered an appropriate treatment option. Therefore the Committee was not persuaded that the comparison of rituximab in combination with fludarabine and cyclophosphamide with chlorambucil was valid as the chemotherapy regimens were used in different populations and such a choice between the two treatments was not expected to be clinically meaningful.

4.8 The Committee reviewed the manufacturer’s economic model and the critique of it by the ERG. The Committee noted that the model was based on all people entering the model in the progression-free survival health state and moving to the progressed health state, and did not allow people to move from the progressed health state to the progression-free survival health state. The Committee was mindful that the economic model allowed for costs of subsequent lines of therapy to be included but noted that this did not allow any benefit from further therapy to be taken into account. More importantly a single transition probability from the progressed health state to death was applied to people from both trial groups in the progressed health state. The Committee recognised that this had the effect of associating improved progression-free survival with improved overall survival. The Committee considered that the assumed association between progression-free survival and overall survival in the model could overestimate the benefits of the clinical effectiveness of rituximab as taken from the CLL-8 trial, because this had not demonstrated a statistically significant difference in overall survival between treatment groups.

4.9 The Committee discussed the analysis by the ERG that suggested that two-thirds of the QALY gain (0.64 out of 0.88) in the model was due to the modelled improvement in overall survival. The Committee noted that when the overall survival benefit was removed from the model the ICER increased from approximately £13,000 to approximately £30,000 per QALY gained. The Committee recognised therefore that the assumption about the amount of gain in overall survival from treatment with rituximab was an important assumption in the economic model and the use of different assumptions could have a large impact on the estimates of cost effectiveness.

4.10 The Committee noted that condition-specific quality of life data collected in the rituximab trial had not been fully reported in the manufacturer’s submission and that the utility values used in the model were not consistent with the NICE reference case because they were not preference-based. The Committee considered that the manufacturer may have been able to map the health-related quality of life data from the rituximab trial to a preference-based measure to derive utilities and that this may have provided an alternative to the utility data used. The Committee noted that, if there was no difference in overall survival between the treatment groups in the model, the results became very sensitive to the difference between the utility values used for the progression-free survival health state and the progressed health state. The Committee considered the lack of appropriate utility data contributed to substantial uncertainty in the economic modelling.

4.11 The Committee discussed the additional exploratory analysis done by the ERG using an assumption that the actual survival benefit from treatment with rituximab was somewhere between that presented base case and an assumption that there was no gain in survival  (see section 3.23). The Committee noted that the probability, using the base-case utilities (that is, 0.80 for the progression-free survival health state and 0.60 for the progressed health state) of rituximab in combination with fludarabine and cyclophosphamide being cost effective at £20,000 per QALY gained was 71% and at £30,000 per QALY gained was 87%. On balance, the Committee was persuaded that even taking into account the additional uncertainty about the utility values, the economic analysis had demonstrated that the use of rituximab in combination with fludarabine and cyclophosphamide for the first-line treatment of people with chronic lymphocytic leukaemia was a cost-effective use of NHS resources. However, the Committee was not persuaded that the cost-effectiveness evidence in the manufacturer’s submission supported the use of rituximab in combination with other chemotherapy agents. In addition the Committee noted the clinical specialists’ statements that in current UK practice rituximab would only be considered in combination with fludarabine and cyclophosphamide when fludarabine in combination with cyclophosphamide is the treatment option of choice. The Committee therefore limited its recommendation to rituximab in combination with fludarabine and cyclophosphamide for people for whom fludarabine in combination with cyclophosphamide is considered an appropriate treatment option.

 

5 Implementation

5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals.

5.2  'Healthcare standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months.

5.3 NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives which support this locally.
• Audit support for monitoring local practice.

 

6 Related NICE guidance

Published

• Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. NICE technology appraisal guidance 119 (2007). Available from www.nice.org.uk/TA119
• Cancer Service Guidance: Improving outcomes in haemato-oncology cancer. NICE clinical guideline (2003). Available from www.nice.org.uk/CSGHO

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Rituximab for relapsed chronic lymphocytic leukaemia. NICE technology appraisal guidance (publication expected August 2010).

7 Proposed date for review of gudiance

7.1 The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider whether the technology should be reviewed. This decision will be taken in the light of information gathered by the Institute, and in consultation with consultees and commentators.

7.2 It is proposed that the guidance on this technology is considered for review in March 2012. The Institute would particularly welcome comment on this proposed date.

David Barnett
Chair, Appraisal Committee
March 2009

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A  Appraisal Committee members

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets three times a month except in December, when there are no meetings. The Committee membership is split into three branches, each with a chair and vice chair. Each branch considers its own list of technologies, and ongoing topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Keith Abrams

Professor of Medical Statistics, University of Leicester

Dr Jeff Aronson

Reader in Clinical Pharmacology, University Department of Primary Health Care, University of Oxford

Dr Darren Ashcroft

Reader in Medicines Usage and Safety, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Professor David Barnett (Chair)

Professor of Clinical Pharmacology, University of Leicester

Professor John Cairns

Public Health and Policy, London School of Hygiene and Tropical Medicine

Dr Mark Chakravarty

External Relations Director - Pharmaceuticals & Personal Health, Oral Care Europe

Professor Jack Dowie

Health Economist, London School of Hygiene and Tropical Medicine

Dr Martin Duerden

Medical Director, Conwy Local Health Board

Dr Fergus Gleeson

Consultant Radiologist, Churchill Hospital, Oxford

Ms Sally Gooch

Independent Nursing and Healthcare Consultant

Mrs Eleanor Grey

Lay member

Mr Terence Lewis

Lay Member, Mental Health Consultant, National Institute for Mental Health in England

Professor Gary McVeigh

Professor of Cardiovascular Medicine, Queens University, Belfast

Dr Ruairidh Milne

Senior Lecturer in Public Health, National Coordinating Centre for Health Technology

Dr Neil Milner

General Practitioner, Tramways Medical Centre, Sheffield

Dr John Pounsford

Consultant Physician, Frenchay Hospital, Bristol

Dr Rosalind Ramsay

Consultant Psychiatrist, Adult Mental Health Services, Maudsley Hospital

Dr Stephen Saltissi

Consultant Cardiologist, Royal Liverpool University Hospital

Dr Lindsay Smith

General Practitioner, East Somerset Research Consortium

Mr Roderick Smith

Finance Director, West Kent Primary Care Trust

Mr Cliff Snelling

Lay Member

Professor Andrew Stevens

Professor of Public Health, Department of Public Health and Epidemiology, University of Birmingham

Ms Nathalie Verin

Health Economics Manager, Boston Scientific UK and Ireland

Dr Colin Watts

Consultant Neurosurgeon, Addenbrookes Hospital

 

B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager

Kim Jeong, Elangovan Gajraj

Technical Leads

Zoe Garrett

Technical Adviser

Jeremy Powell

Project Manager

 

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by the Peninsula Technology Assessment Group, University of Exeter:

• Main C, Moxham T, Pitt M and Stein K, "The clinical and cost-effectiveness of Rituximab for the 1st line treatment of Chronic Lymphocytic Leukaemia: an evidence review of the submission from Roche" January 2009

B The following organisations accepted the invitation to participate in this appraisal. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Roche Products

II Professional/specialist and patient/carergroups:

• British Society forHaematology
• Cancer Research UK
• Chronic LymphocyticLeukaemia Support Association
• LeukaemiaCARE
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians, Medical Oncology Joint Special Committee
• Royal College of Radiologists
• United Kingdom CLL Forum

III  Other consultees

• Department of Health
• Hampshire Primary Care Trust
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal)

• Bayer
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Pharmacia

C The following individuals were selected from clinical specialist and patient advocate nominations from the non-manufacturer/sponsorconsultees and commentators. They gave their expert personal view onrituximab for first line chronic lymphocytic leukaemia by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Donald Milligan, Consultant Haematologist, NCRI, nominated by the Royal College of Physicians – clinical specialist
• Professor AndrewPettitt, Professor of Haematology, University of Liverpool, nominated by the Royal College of Pathologists
• Mrs Jane Barnard, nominated by the Chronic Lymphocytic Leukaemia Support Association – patient expert
• Mrs Jacquelyn Williams Durkin, nominated by theChronic Lymphocytic Leukaemia Support Association – patient expert